Lacosamide and process for its preparation was first disclosed in U.S. Pat. No. 5,773,475. Different routes of synthesis for the preparation of Lacosamide have been reported in literature like U.S. Pat. No. 6,048,899, US 2008/027137 and US 2009/143472 and Tetrahedron Asymmetry 1998, 9, 3841-3854.
Lacosamide and process for its preparation was first disclosed in U.S. Pat. No. 5,773,475. The disclosed process involves O-methylation of (R)-2-acetamido-N-benzyl-3-hydroxy propanamide by reacting it with methyl iodide in presence of silver oxide in acetonitrile. The said process involves the usage of costly reagent like silver oxide and methyl iodide for O-methylation increases the cost of production and hence usage of the same in commercial scale is not possible. Moreover lacosamide obtained by the said process contaminated with more impurities. Hence there is a need in the art for the cost effective process preparation of pure lacosamide which involves the usage of simple and cost effective reagent.
Another process was disclosed in Tetrahedron Asymmetry 1998, 9; 3841-3854. The disclosed process involves the reaction of D-Serine with Benzylchloroformate and MgO in diethyl ether to provide (R)—N-(benzyloxycarbonyl)serine, which on further treatment with benzylamine in presence of 4-methylmorpholine and isobutyl chloroformate in THF provides (R)—N-benzyl-2-N(BenzyloXycarbonyl)amino-3-hydroxypropionamide. Thus obtained hydroxy intermediate was methylated by treating with methyl iodide in presence of silver oxide in acetonitrile to provide (R)—N-benzyl-2-N-(Benzyloxycarbonyl)amino-3-methoxypropionamide. Deprotection of the N-protecting group from the obtained methoxy derivative by hydrogenation in presence Pd/C catalyst in methanol provides (R)—N-benzyl-2-amino-3-propionamide, which on Acetylation with acetic anhydride in presence of DMAP and pyridine in THF gives Lacosamide.
The said process has number of disadvantages and hence is difficult to carry out in commercial scale. 1) It involves the usage of MgO and ether solvent for the N-protection of D-serine. The usage of ether solvent and MgO at commercial level is not recommendable. 2) It involves the usage of costly reagent like silver oxide and methyl iodide for O-methylation increases the cost of production and hence usage of the same in commercial scale is not possible. 3) Further it involves the usage of hydrogenation in presence of Pd/C catalyst for deprotection of N-protecting group to get lacosarriide. The usage of Pd/C in commercial level is difficult to handle in safety aspect and increase the cost of production. Hence there is a need in the art for an improved process for the preparation of lacosamide which avoids all the problems mention here.
Later US patent publication US 2008/0027137 disclosed a process for the preparation of (R)-2-((t-butoxy)carbonylamino)-3-methoxypropanoic acid and its conversion to lacosamide. The disclosed process involves the protection of D-serine with di-t-butyl dicarbonate to provide N-Boc-D-serine, which is further O-methylated using dimethylsulphate to provide (R)-2-((t-butoxy)carbonylamino)-3-methoxy propanoic acid. Both the protection and O-methylation reaction were carried in a biphasic solvent system such as in a mixture of toluene & water, in presence of phase transfer catalyst and a base. Even though the disclosed process provides good yield, it involves the usage of costly reagent such as phase transfer catalyst, which increases the cost of production.
It has now surprisingly found by the present inventors that both the protection and O-methylation reaction has been carried out in a single phase solvent system without using costly phase transfer catalyst with good yields and purity, there by reduces the cost of production. The present invention provides an improved process for the preparation of lacosamide, wherein the O-methylation of N-Boc-D-serine and protection of D-serine with di-t-butyl dicarbonate were carried out in a single phase solvent system without usage of phase transfer catalyst.
The main aspect of the present invention is to provide a cost effective process for the preparation of lacosamide which avoids the problems associated with the prior art processes.